Measles, mumps and rubella are three common childhood diseases that are caused by viral infection (by measles virus (a paramyxovirus), mumps virus (a paramyxovirus), and rubella virus (a togavirus), respectively). Measles, mumps and rubella infections may cause serious medical complications which may lead to death. Measles is an infection of the respiratory system and causes symptoms including fever, cough, runny nose, and general rash, and commonly leads to complications such as pneumonia and encephalitis. Mumps is an infection that causes symptoms including inflammation, fever, headache and orchitis, and can lead to complications such as aseptic meningitis and deafness. Rubella, commonly known as German measles, generally causes mild symptoms, although infection of a mother during pregnancy can be quite serious.
Vaccines against measles, mumps and rubella are produced from live attenuated viruses which have been propagated in cell substrates. Each component of MMR vaccine is initially prepared in the monovalent form, each of which is then mixed together to produce a trivalent form in which the component virus population is present in a well defined quantity sufficient to induce an effective immune response in a vaccine recipient. The marketed MMR vaccines are presented as a lyophilized vial, which has to be kept at 2-8° C. for no more than 3 years as per the licensure indications. However several factors including stabilizer composition, storage conditions and residual moisture can affect the thermal stability of the lyophilized vaccine. The World Health Organization (WHO) recommends tissue culture infective doses (TCID50) assay using Vero cells for evaluating potency of live measles virus in the vaccine. However, the potency measurements may vary depending on the method of determination, the laboratory, and the conditions at the time of the test.
WHO has set up minimum requirements for vaccine stability in freeze dried form as well as when reconstituted as a liquid solution prior to administration. In the freeze dried state, current measles vaccines must retain a minimum potency of at least 3.0 log10 virus particles per human dose after exposure to a temperature of 37° C. for at least one week and the virus titre dose not decrease by more than 1.0 log10 during incubation. However, reconstituted measles vaccines quickly lose potency at exposure to room temperatures. At 22° C. to 25° C. the vaccine loses approximately 50% of potency in one hour. At temperatures over 37° C. the vaccine is inactivated within one hour (The Immunological Basis for Immunization Series, Module 7: Measles (WHO/EPI/GEN/93.17).
Several attenuated measles, mumps and rubella (MMR) vaccines are currently licensed and have been successful in reducing the incidence of viral infection. However, all vaccines, including attenuated virus vaccines, lose potency over time and the rate of potency loss is temperature-dependent. Therefore, cold-chain systems have been established to ensure that the potency of vaccines is maintained by storing them under refrigerated conditions (in most cases between 2 and 8° C.) until the point of use. Establishing a cold chain for vaccine storage and distribution is a major undertaking and maintenance is difficult. It is also apparent that, despite best efforts, cold chains do not always function as intended for many reasons, such as improperly maintained or outdated refrigeration equipment, power outages resulting in equipment failure, poor compliance with cold-chain procedures and inadequate monitoring. The result is that vaccines in the cold chain are often subjected to temperature excursions (i.e., temperatures outside of the target range).
While attenuated measles, mumps and rubella (MMR) vaccines have been successful in reducing the incidence of disease worldwide, there remains a need in the art for improved vaccines that are stable and retain potency when exposed to high temperatures.